A Review on Drug - drug Interaction Studies of Spiranolactone and Telmisartan
G. Swapna, J. Poojitha*, B. Pravallika
Department of Pharmaceutical Analysis, Nirmala College of Pharmacy, Atmakuru, Guntur District -522503
*Corresponding Author E-mail: poojithajammalamudi97@gmail.com
ABSTRACT:
A drug interaction is a change in the action or side effects of a drug caused by concomitant Administration with a food, beverage, supplement, or another drug. There are many causes of drug interactions. For example, one drug may alter the pharmacokinetics of another. Alternatively, drug interactions may result from competition for a single receptor or signalling pathway. The risk of a drug-drug interaction increases with the number of drugs used. Over a third (36%) of the elderly in the U.S. regularly use five or more medications or supplements, and 15% are at potential risk of a significant drug-drug interaction. Drug interactions can have desired, reduced or unwanted effects. The probability of interactions increases with the number of drugs taken. The high rate of prescribed drugs in elderly patients (65-year-old patients take an average of 5 drugs) increases the likelihood of drug interactions and thus the risk that drugs themselves can be the cause of hospitalization. There are many causes of drug interactions. For example, one drug may alter the pharmacokinetics, absorption, distribution, metabolism, or excretion (ADME) of another. The risk of a drug interaction occurring increases as the number of drugs administered to a patient increases. Similarly the drug interaction studies of spiranolactone which is a potassium-sparing diuretics and telmisartan which is an angiotensin receptor blockers is known in this. And the qualitative and quantitative analysis of the two drugs is also studied in this.
KEYWORDS: Spiranolactone, telmisartan, validation, stability study, RP-HPLC, LC-MS.
INTRODUCTION:
Telmisartan, sold under the trade name Micardis among others, is a medication used to treat high blood pressure, heart failure, and disease1. It is a reasonable initial treatment for high blood pressure1. It is a angiotensin II receptor antagonist and works by blocking the effects of angiotensin II1. Telmisartan was patented in 1991 and came into medical use in 19992.
It is available as a generic medication3. Telmisartan blocks the angiotensin receptor by blocking the action of angiotensin, telmisartan widens blood vessels (vasodilator) and reduces blood pressure, Telmisartan was approved by the FDA in November 20004. Telmisartan, an angiotensin II receptor blocker, as well as having a terminal elimination half-life of 24hrs, has a large volume of distribution due to its high lipophilicity.5 Telmisartan is an angiotensin II receptor antagonist (ARB) used in the management of hypertension. Generally, angiotensin II receptor blockers (ARBs) such as telmisartan bind to the angiotensin II type 1 (AT1) receptors with high affinity, causing inhibition of the action of angiotensin II on vascular smooth muscle, ultimately leading to a reduction in arterial blood pressure. Recent studies suggest that telmisartan may also have PPAR-gamma agonistic properties that could potentially confer beneficial metabolic effects6. Spironolactone was discovered in 1957 and was introduced in 19597. It was sold under the name Aldactone among others, is a medication that is primarily used to treat fluid build-up due to heart failure, liver scarring, or kidney disease8. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system9. Spironolactone is used primarily to treat heart failure, edematous conditions such as nephrotic syndrome or ascites in people with liver disease, essential hypertension, low blood levels of potassium, secondary hyperaldosteronism, and Conn's syndrome. Spironolactone is a potassium-sparing diuretic. Sometimes called "water pills," diuretics help the kidneys expel water and salt in urine while retaining potassium. The most common use of spironolactone is in the treatment of heart failure10.
Fig no:1 Telmisartan Fig no:2 Spiranolactone
SIDE EFFECTS:
Telmisartan has the following side effects like tachycardia, bradycardia (fast or slow heartbeat), hypotension (low blood pressure), oedema (swelling of arms, legs, lips, tongue, or throat, the latter leading to breathing problems)11dizziness or light-headedness may occur as your body adjusts to the medication, blurred vision, stuffy nose, sinus pain, diarrhoea, skin rashes12. spiranolactone has the following side effects like urinary frequency. Other general side effects includes dehydration, hyponatremia (low sodium levels), mild hypotension (low blood pressure)13. Ataxia (muscle incoordination), drowsiness, dizziness14. The most important potential side effect of spironolactone is hyperkalemia (high potassium levels), which, in severe cases, can be life-threatening. Hyperkalemia in these people can present as a non anion-gap metabolic acidosis. spironolactone may put people at a heightened risk for gastrointestinal issues like nausea, vomiting, diarrhoea, cramping, and gastritis. in addition, there has been some evidence suggesting an association between use of the medication and bleeding from the stomach and duodenum, though a causal relationship between the two has not been established15.
USES:
The quantitative NMR (qNMR) spectroscopy is nowadays a new tool for the determination of pharmaceutical potent biologically active molecules in bulk drug and its tablet formulation than the other analytical techniques. Herein, qNMR method was developed for an anti‐hypertensive drug, telmisartan in bulk drug and its tablet formulation. The precise method was developed by using malononitrile as an internal standard. The methylene signal of telmisartan appeared at δ = 5.46 ppm (singlet) relative to the signal of malononitrile at δ = 3.59 ppm (singlet) in CDCl3, as an NMR solvent. The development and validation of the method were carried out as per International Conference on Harmonization guidelines. The method was found to be linear (r2 = 0.9999) for 0.5 to 3.5 mg/ml in the drug concentration range. The relative standard deviation for accuracy and precession was not more than 2.0%. The sensitivity of the method was carried out by limit of detection and a limit of quantification, at 0.05 and 0.2 mg/ml, respectively, concentration. The robustness of the method was studied by changing parameters as well as different solvent manufacturer company. The result shows that method was accurately developed for quantification of telmisartan in pharmaceutical dosage form. The developed method by 1H NMR spectroscopy is comparatively easy and more precise with respect to the other analytical tools.
Validated RP-HPLC Method for Simultaneous Determination of Telmisartan and Hydrochlorothiazide in Pharmaceutical Formulation21:
A simple, precise and rapid stability-indicating ultra-performance liquid chromatography (UPLC) method is developed for the simultaneous quantitative determination of Telmisartan, Amlodipine besylate and Hydrochlorothiazide from their innovative poly pill combination drug product in the presence of degradation products. It involves a 100mm x 2.1mm, 1.7μm C-18 column. The separation is achieved on a simple gradient method. The mobile phase A contains a mixture of sodium perchlorate buffer pH 3.2 (0.053M): acetonitrile in the ratio 90:10, v/v, and mobile B contains a mixture of sodium perchlorate buffer pH 3.2 (0.053M): acetonitrile in the ratio 20:80, v/v. The flow rate is 0.6 mL min−1 and the column temperature is maintained at 55°C. The gradient program (T/%B) is set as 0/5, 1.2/5, 1.6/40, 4/40, 4.1/5 and 4.5/5. The detector wavelength is 271nm for Hydrochlorothiazide and Telmisartan and 237 nm for Amlodipine. The retention times of Telmisartan, Amlodipine, and Hydrochlorothiazide are 3.6minutes, 3.2minutes and 0.9minutes; respectively. The total runtime for the separation of the three active compounds and their degradation products is 4.5minutes. The described method is validated with respect to system suitability, specificity, linearity, precision and accuracy. The precision of the assay method is evaluated by carrying out six independent assays of T, A and H (0.032 mg mL−1 of T, 0.004 mg mL−1 of A, 0.01 mg mL−1 of H). The accuracy of the method is evaluated in triplicate at three concentration levels, i.e. 50%, 100% and 150% of target test concentration (0.64 mg mL−1 of T, 0.08 mg mL−1 of A, 0.2 mg mL−1 of H). The described method is linear over the range, 16 to 48μg mL−1 for T, 2 to 6μg mL−1A and 5 to 15μg mL−1 for H. The method is fast and suitable for high-throughput analysis allowing the analysis of about 250 samples per working day.
A simple, validated RP-HPLC method for the simultaneous estimation of Amlodipine Besylate and Telmisartan in pharmaceutical dosage form and bulk was developed for routine analysis. This method was developed by selecting Chromosil C18 (250×4.6mm column as stationary phase and ACN: MeOH: water (65: 30: 5 v/v/v) as mobile phase. Flow rate of mobile phase was maintained at 1ml/min at ambient temperature throughout the experiment. Quantification was achieved with ultraviolet (DAD) detection at 240nm. The retention times of Amlodipine Besylate and Telmisartan were found as 4.56 min and 6.59 min respectively. The detector response was linear in the concentration range of 2-20µg/ml and 16-160µg/ml, has regression coefficients 0.998 and 0.999 for Amlodipine Besylate and Telmisartan respectively. From recovery studies we concluded that the recovery of amlodipine besylate and telmisartan has no interference with any excepients in the formulation. This method has been validated according to ICH guidelines and shown to be Specific, Sensitive, Precise, Accurate, Rugged and Robust. Hence, this method can be applied for routine quality control of Amlodipine Besylate and Telmisartan in dosage forms as well as in bulk drug
An economical, precise, rapid and accurate RP-HPLC method has been developed for the simultaneous estimation of Olmesartan Medoxomil and Cilnidipine in bulk and tablet dosage form. Separation was carried out on Jasco HPLC system equipped with HiQ sil C18 column (250×4.6 mm i.d.) and PDA detector using Methanol: 40mM Potassium dihydrogen ortho phosphate buffer (90:10 v/v) as the mobile phase. Ortho-phosphoric acid was used to adjust pH to 3.0, and detection was carried out at 254 nm. Results were linear in the range of 5-30 μg/ml for Cilnidipine and 10-50 μg/ml for Olmesartan Medoxomil respectively. The method was successfully applied for the analysis of drugs in pharmaceutical formulation. Results of the analysis were validated statistically and by recovery studies.
Stability-indicating methods for the quantitative determination of spironolactone were developed. The methods are based on high-pressure liquid chromatography and a reaction with blue tetrazolium. Both methods are accurate, precise, and sensitive and gave excellent results with commercial tablets, including those containing hydrochlorothiazide in addition to spironolactone, The blue tetrazolium method cannot be used in the presence of high concentrations of either polyethylene glycols or water. Spironolactone decomposition in water or polyethylene glycol appears to follow pseudo-first-order kinetics. The decomposition constant at 65 degrees was 0.0253/day in water versus 0.115/day in polyethylene glycol ointment base USP.
Analysis of spironolactone polymorphs in active pharmaceutical ingredients and their effect on tablet dissolution profiles26:
Spironolactone (SPR) is a steroidal drug administered as a potassium-sparing diuretic for high blood pressure treatment. The drug shows incomplete gastrointestinal absorption due to its poor aqueous solubility. The physicochemical properties of SPR in crystal forms I and II suggest that differences in their aqueous solubility may lead to a lack of bioequivalence between solid-state formulations. In this study, SPR polymorphs in five batches of active pharmaceutical ingredients (APIs) from three manufacturers were characterized using powder X-ray diffraction, infrared spectroscopy, thermal analysis, and solubility measurements. SPR tablets (50 mg) were manufactured in our laboratory using API in pure form II, and API in form II contaminated with form I, which was found in a commercial batch. Physicochemical quality evaluations of the manufactured tablets, along with five SPR tablets marketed in Brazil, were performed, and results indicated differences in their dissolution profiles. In the manufactured tablets, differences were associated with the increased solubility of API in form II contaminated with form I compared to API in pure form II. In the marketed SPR tablets, the formulation composition demonstrated an important role in the dissolution rate of the drug, leading to lack of pharmaceutical equivalence among the drug products.
Schistosomiasis is a parasitic flatworm disease that infects over 200 million people worldwide, especially in poor communities. Treatment and control of the disease rely on just one drug, praziquantel. Since funding for drug development for poverty-associated diseases is very limited, drug repurposing is a promising strategy. In this study, from a screening of 13 marketed diuretics, we identified that spironolactone, a potassium-sparing diuretic, had potent antischistosomal effects on Schistosoma mansoni in vitro and in vivo in a murine model of schistosomiasis. In vitro, spironolactone at low concentrations (<10 µM) is able to alter worm motor activity and the morphology of adult schistosomes, leading to parasitic death. In vivo, oral treatment with spironolactone at a single dose (400 mg/kg) or daily for five consecutive days (100 mg/kg/day) in mice harboring either patent or prepatent infections significantly reduced worm burden, egg production, and hepato- and splenomegaly (P < 0.05 to P < 0.001). Taken together, with the safety profile of spironolactone, supported by its potential to affect schistosomes, these results indicate that spironolactone could be a potential treatment for schistosomiasis and make it promising for repurposing.
Simultaneous Identification and Quantification of Canrenone and 11-α-Hydroxy-Canrenone by LC-MS and HPLC-UVD29:
A procedure for simultaneous identification and quantification of canrenone and its biotrans formed product 11-α-hydroxy-canrenone by high-performance liquid chromatography with ultraviolet detector (HPLC-UVD) and mass spectrometry (LC-MS) methods was proposed. The optimal determination variables on the HPLC-UVD or LC-MS coupled with a ZORBAX Eclipse XDB-C18 column (150 mm×4.6 mm, 5 μm) were set as follows: detection wavelength of 280 nm, mobile phase of water and methanol gradient elution, temperature for the chromatographic column of 30°C, flow rate of mobile phase of 0.8 mL/min, sample injection volume of 5μL, and elution time of 40 min. The MS conditions were set as follows: the flow rate of sheath gas, aux gas, and sweep gas were kept at 35 arb, 5 arb, and 0 arb, respectively. The temperature of capillary was held at 300°C, and capillary voltage was set at 30.00 V. Tube lens were performed at 100.00 V. The proposed method was validated by linearity ( ≥ 0.9910), average recovery (94.93%, RSD1.21%), precision (RSD ≤ 1.31%), limit of detection, and limit of quantification (LOD 0.1~0.12 mg/L, LOQ 0.5~0.67 mg/L), which proved to be affordable for simultaneously determining canrenone and its bio-transformed product 11-α-hydroxy-canrenone.
DISCUSSION:
Drug-Drug Interactions of Telmisartan and Spiranolactone in which we confirmed that RP-HPLC Method was mostly used and secondly HPLC method was used. In This we confirmed that RP-HPLC methods such as Validated RP-HPLC Method for Simultaneous Determination of Telmisartan and Hydrochlorothiazide in Pharmaceutical Formulation, Development and validation of RP-HPLC method for the simultaneous determination of amlodipine besylate and telmisartan in bulk and pharmaceutical dosage forms, Development and validation of analytical method for simultaneous estimation of cilnidipine and Olmesartan medoxomil in bulk and tablet dosage form by RP-HPLC are used. Simultaneosly for HPLC method like Simultaneous Identification and Quantification of Canrenone and 11-α-Hydroxy-Canrenone by LC-MS and HPLC-UVD, Stability-indicating methods for quantitative determination of spironolactone using high-pressure liquid chromatography and blue tetrazolium reaction are discussed.
ACKNOWLEDGEMENTS:
The authors are thankful to Nirmala College of Pharmacy for providing the facilities to publish a Review Article.
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Received on 05.09.2019 Modified on 30.09.2019
Accepted on 15.10.2019 ©A&V Publications All right reserved
Res. J. Pharmacology & Pharmacodynamics.2019; 11(4):153-158.
DOI: 10.5958/2321-5836.2019.00027.2